On 2015 Oct 27, Peter Gøtzsche commented:

This review concludes that, “The three cholinesterase inhibitors are efficacious for mild to moderate Alzheimer’s disease.” I believe these drugs don’t work. The improvement in cognitive function was 2.7 points, in the midrange of a 70-point scale. This is less than the 4 points the FDA considers the minimally relevant clinical chan¬ge (1). We can also compare with the smallest effect that can be per¬ceived on the Hamilton scale for depression, which is 5-6 (2), although the maximum on this scale is only 52.

The placebo controlled trials have not been effectively blinded, as cholinesterase inhibitors have conspicuous side effect. This lack of blinding can in itself easily have caused the very minor effect that was noted in the trials (3).

A long-term trial of 565 patients with mild to moderate Alz¬heimer’s disease that compared donepezil with placebo found no meaningful effects whatsoever, and the authors concluded that do¬nepezil isn’t cost-effective, with benefits below minimally relevant thresholds (4). In contrast to other trials, it was publicly funded. This trial was excluded from the Cochrane review, for no good reason, as far as I can see. The outcomes after three years were similar on drug and placebo with respect to institutionalisation, progression of disability, and behavioural and psychological symptoms.

The author of the Cochrane review wrote that “donepezil appears to have no serious or common side effects.” This sentence is highly misleading. The harms are both common and serious, and she documents in her review that 29% of the patients left the drug group on account of adverse events, as compared to only 18% in the placebo groups. The most common side effects of donepezil are nausea, diarrhoea, not sleeping well, vomiting, muscle cramps, feeling tired, and not wanting to eat. I believe this is not what we would want for an old person who might already have problems with not sleeping well, feeling tired, and not wanting to eat.

The list of frequent side effects in Pfizer’s product information for Aricept (donepezil) is very long (5). Hypotension and syncope occurs in more than 1% and when old people fall, there is a considerable risk that they break their hip and die. A large Canadian cohort study showed that people who took anti-dementia drugs had almost a doubled risk of hospitalisation for syncope compared to demented people who didn’t take these drugs, and they had more pacemakers inserted and more hip fractures (6). Most astonishingly, more than half the patients who were admitted to hospital for bradycardia were retreated with the drug.

There are many good reasons not to use anti-dementia drugs.

1 Molnar FJ, Man-Son-Hing M, Fergusson D. Systematic review of measures of clinical significance employed in randomized controlled trials of drugs for de¬mentia. J Am Geriatr Soc 2009;57:536-46.

2 Leucht S, Fennema H, Engel R, et al. What does the HAMD mean? J Affect Disord 2013;148:243-8.

3 Gøtzsche PC. Deadly psychiatry and organised denial. Copenhagen: People’s Press; 2015.

4 Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105-15.

5 ARICEPT ® (donepezil hydrochloride) tablets. http://labeling.pfizer.com/ShowLabeling.aspx?id=510.

6 Syncope with cholinesterase inhibitors. Rev Prescrire 2011;31:434.

On 2015 Oct 27, Peter Gøtzsche commented:

This review concludes that, “The three cholinesterase inhibitors are efficacious for mild to moderate Alzheimer’s disease.” I believe these drugs don’t work. The improvement in cognitive function was 2.7 points, in the midrange of a 70-point scale. This is less than the 4 points the FDA considers the minimally relevant clinical chan¬ge (1). We can also compare with the smallest effect that can be per¬ceived on the Hamilton scale for depression, which is 5-6 (2), although the maximum on this scale is only 52.

The placebo controlled trials have not been effectively blinded, as cholinesterase inhibitors have conspicuous side effect. This lack of blinding can in itself easily have caused the very minor effect that was noted in the trials (3).

A long-term trial of 565 patients with mild to moderate Alz¬heimer’s disease that compared donepezil with placebo found no meaningful effects whatsoever, and the authors concluded that do¬nepezil isn’t cost-effective, with benefits below minimally relevant thresholds (4). In contrast to other trials, it was publicly funded. This trial was excluded from the Cochrane review, for no good reason, as far as I can see. The outcomes after three years were similar on drug and placebo with respect to institutionalisation, progression of disability, and behavioural and psychological symptoms.

The author of the Cochrane review wrote that “donepezil appears to have no serious or common side effects.” This sentence is highly misleading. The harms are both common and serious, and she documents in her review that 29% of the patients left the drug group on account of adverse events, as compared to only 18% in the placebo groups. The most common side effects of donepezil are nausea, diarrhoea, not sleeping well, vomiting, muscle cramps, feeling tired, and not wanting to eat. I believe this is not what we would want for an old person who might already have problems with not sleeping well, feeling tired, and not wanting to eat.

The list of frequent side effects in Pfizer’s product information for Aricept (donepezil) is very long (5). Hypotension and syncope occurs in more than 1% and when old people fall, there is a considerable risk that they break their hip and die. A large Canadian cohort study showed that people who took anti-dementia drugs had almost a doubled risk of hospitalisation for syncope compared to demented people who didn’t take these drugs, and they had more pacemakers inserted and more hip fractures (6). Most astonishingly, more than half the patients who were admitted to hospital for bradycardia were retreated with the drug.

There are many good reasons not to use anti-dementia drugs.

1 Molnar FJ, Man-Son-Hing M, Fergusson D. Systematic review of measures of clinical significance employed in randomized controlled trials of drugs for de¬mentia. J Am Geriatr Soc 2009;57:536-46.

2 Leucht S, Fennema H, Engel R, et al. What does the HAMD mean? J Affect Disord 2013;148:243-8.

3 Gøtzsche PC. Deadly psychiatry and organised denial. Copenhagen: People’s Press; 2015.

4 Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105-15.

5 ARICEPT ® (donepezil hydrochloride) tablets. http://labeling.pfizer.com/ShowLabeling.aspx?id=510.

6 Syncope with cholinesterase inhibitors. Rev Prescrire 2011;31:434.